Vascular disease is a pathological state of large and medium sized muscular arteries and is triggered by endothelial cell dysfunction. Because of factors like pathogens, oxidized LDL particles and other inflammatory stimuli, endothelial cells become activated. This leads to changes in their characteristics: endothelial cells start to excrete cytokines and chemokines and express adhesion molecules on their surface. This in turn results in recruitment of white blood cells (monocytes and lymphocytes), which can infiltrate the blood vessel wall. Stimulation of the smooth muscle cell layer with cytokines produced by endothelial cells and recruited white blood cells causes smooth muscle cells to proliferate and migrate towards the blood vessel lumen. This process causes thickening of the vessel wall, forming a plaque consisting of proliferating smooth muscle cells, macrophages and various types of lymphocytes. This plaque results in obstructed blood flow leading to diminished amounts of oxygen and nutrients, that reach the target organ. In the final stages, the plaque may also rupture causing the formation of clots, and as a result, strokes.
Respiratory disease is a medical term that encompasses pathological conditions affecting the organs and tissues that make gas exchange possible in higher organisms, and includes conditions of the upper respiratory tract, trachea, bronchi, bronchioles, alveoli, pleura and pleural cavity, and the nerves and muscles of breathing. Respiratory diseases range from mild and self-limiting, such as the common cold, to life-threatening entities like bacterial pneumonia, pulmonary embolism, and lung cancer.
Pulmonary arterial hypertension (PAH) is a rare vascular disease for which there is currently no cure. Heritable and idiopathic pulmonary arterial hypertension (PAH) are characterized by narrowing and obliteration of precapillary pulmonary arteries, secondary to proliferation and apoptosis resistance of smooth muscle cells, fibroblasts and endothelial cells (Morrell et al (2009) J Am Coll Cardiol 54, S20-31). The resulting increase in pulmonary vascular resistance causes severe elevation of pulmonary artery pressure, leading to right ventricular hypertrophy and ultimately death from right heart failure (Gaine and Rubin (1998) Lancet 352, 719-725).
The identification of heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II receptor (BMPR-II) in 2000 (Lane et al Nat Genet 26, 81-84 (2000); Deng et al (2000) Am J Hum Genet 67, 737-744) provided major insight into the pathobiology of heritable PAH. Subsequent studies have also identified BMPR-ll mutations in 15-40% of cases of idiopathic PAH (Thomson et al (2000) J Med Genet 37, 741-745), as well as reduced expression of BMPR-II as a feature of non-genetic forms of PAH in humans (Atkinson et al (2002) Circulation 105, 1672-1678) and animal models (Long et al (2009) Circulation 119, 566-576).
Genetic evidence also strongly implicates the endothelial cell as the key initiating cell type in PAH. Previous studies have shown that conditional deletion of BMPR-II in the endothelium is sufficient to induce PAH in a proportion of mice (Hong et al (2008) Circulation 118, 722-730) and that rescue of endothelial BMPR-II signaling in rodent models prevents or reverses experimental pulmonary hypertension (Reynolds et al (2012) Eur Respir J 39, 329-343; Reynolds et al (2007) Am J Physiol Lung Cell Mol Physiol 292, L1182-1192; Spiekerkoetter et al (2013) J Clin Invest 123, 3600-3613). More recently, it has been shown that selective enhancement of endothelial BMPR-II with BMP9 reverses pulmonary arterial hypertension (Long et al (2015) Nature Medicine 21, 777-785). In addition, mutations have now been reported in the type I receptor, ALK-1 (Trembath et al (2001) N Engl J Med 345, 325-334), and the type III receptor accessory protein, endoglin (Harrison et al (2003) J Med Genet 40, 865-871), in patients with PAH, both of which are almost exclusively expressed on the endothelium. Despite this evidence, the precise nature of the endothelial dysfunction in the pathobiology of PAH and the involvement of BMP signaling in this process remain points of contention. Although established PAH is characterized by the excessive clonal proliferation of pulmonary endothelial cells (Yeager et al (2001) Circ Res 88, E2-E11) as a component of obstructive cellular lesions, the initiation of disease pathology in both humans (Teichert-Kuliszewska et al (2006) Circ Res 98, 209-217) and animal models of disease (Wilson et al (1992) Crit Rev Toxicol 22, 307-325; Taraseviciene-Stewart et al (2001) Faseb J 15, 427-438) has been linked to a paradoxical increase in endothelial cell apoptosis. Additional studies have identified a role for endothelial BMPR-II loss in the exacerbation of vascular permeability and the altered translocation of leukocytes across the vascular wall (Burton et al (2011) Blood 117, 333-341; Burton et al (2011) Blood 118, 4750-4758; Kim et al (2013) Arterioscler Thromb Vasc Biol 33, 1350-1359).
While in vitro studies using pulmonary artery smooth muscle cells (PASMCs) have demonstrated that increasing concentrations of BMP ligand can overcome the loss of function associated with mutations in the BMP signaling pathway (Yang et al (2008) Circ Res 102, 1212-1221), to date, no study has therapeutically delivered BMP ligand in vivo to provide proof-of-concept for such an approach in the treatment of PAH. The complexity of the BMP signaling family, which is comprised of four type-II receptors, five type-I receptors and over twenty BMP ligands (Miyazono et al (2005) Cytokine Growth Factor Rev 16, 251-263), may account for the absence of such studies. Identifying an appropriate ligand to selectively target the pulmonary endothelium presents a significant challenge. Recently, BMPR-II was found to form a signaling complex with ALK-1 and signal specifically in response to BMP9 and 10 in microvascular endothelial cells (David et al (2007) Blood 109, 1953-1961).
WO 2005/113590 describes the use of BMP10 antagonists for the treatment of heart disorders. WO 201 3/1 5221 3 describes the use of BMP9 and/or BMP 10 polypeptides for increasing red blood cell and/or hemoglobin levels in vertebrates. WO 2006/130022 describes an agonist or antagonist of BMPRII which is useful in the modulation of folliculogenesis and ovulation rate in female mammals. WO 2010/114833 describes pharmaceutical compositions for treating heart disease that include a bone morphogenetic protein. WO 94/26893 describes BMP-10 proteins, processes for producing them and their use in the treatment of bone and cartilage defects and in wound healing and related tissue repair. WO 95/24474 and WO 96/39431 describe the human BMP-10 polypeptide and DNA (RNA) encoding such polypeptide which are claimed to be useful in inducing de novo bone formation. WO 93/00432 and WO 95/33830 describe BMP-9 proteins, processes for producing them and their use in the treatment of bone and cartilage defects, wound healing and related tissue repair and in hepatic growth and function. WO 2010/115874 describes methods for treating pulmonary arterial hypertension by administering apelin/APJ targeting drugs. WO 2009/114180 and WO 2014/160203 describe small molecule inhibitors of BMP signaling which are claimed to be useful in the modulation of cell growth, differentiation, proliferation, and apoptosis, and thus may be useful for treating diseases or conditions associated with BMP signaling, including inflammation, cardiovascular disease, hematological disease, cancer, and bone disorders, as well as for modulating cellular differentiation and/or proliferation. The small molecule inhibitors are also claimed to be useful in reducing circulating levels of ApoB-100 or LDL and treating or preventing acquired or congenital hypercholesterolemia or hyperlipoproteinemia; diseases, disorders, or syndromes associated with defects in lipid absorption or metabolism; or diseases, disorders, or syndromes caused by hyperlipidemia.
There is therefore a need to provide an effective treatment for vascular and respiratory diseases, in particular pulmonary arterial hypertension (PAH).